Polydehydro 17alpha-ethynylestran-17beta-ols and esters



United States Patent 3,436,412 POLYDEHYDRO 17a-ETHYNYLESTRAN-17fi-0LS AND ESTERS Leland J. Chinn, Morton Grove, Ill., assignor to G. D. Searle & Co., Chicago, Ill., a corporation of Delaware N0 Drawing. Filed Sept. 26, 1966, Ser. No. 581,702 Int. Cl. C07c 169/ 08, 169/12 US. Cl. 260397.5 Claims This invention relates to polydehydro 17a-ethynylestran- 175-015 and esters substituted in the 3-position by a monovalent hydrocarbon radical, and to processes for the preparation thereof. More particularly, this invention relates to compounds of the formula preparable by (1) the Grignard reaction of 17a-ethynyl- 17fl-hydroxyestra-4,9-dien-3-one [J. Amer. Chem. Soc., 82, 2402 (1960)] with a magnesium bromide of the formula (2) esterification of the product of (1) with acetic anhydride in pyridine, and (3) saponification of the product of (2) with methanolic potassium hydroxide, as illustrated in the working examples hereafter. In the foregoing formula(s), R represents hydrogen or an acetyl radical, R" represents a lower alkyl or phenyl radical, and the dotted lines indicate that the compounds are A or A901) and can also be A The compounds to which this invention relates are useful by reason of their valuable pharmacological properties. For example, they lower plasma cholesterol levels in hypercholesterolemic animals; they are also estrogenic.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their preparation. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

Example 1 17a ethynyl 3 methylestra 3,5 (10),9(11) trien- 17fl-ol.To a solution of approximately 90 parts of methylmagnesium bromide in 175 parts of anhydrous ether is added, with stirring under reflux at a rate such that gentle boiling is maintained, a solution of 4 parts of 170: ethynyl 17,8 hydroxyestra-4,9(11)-dien-3-one in a mixture of 45 parts of tetrahydrofuran and 35 parts of anhydrous ether. When the addition is complete, stirring is continued while the reactants are heated at the boiling point under reflux for 6 hours, then chilled, and finally diluted with an equal volume of ice water. The resultant mixture is acidified with approximately 20% hydrochloric acid. The organic phase is separated, washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual viscous oil is chromatographed on silica gel. Elution with benzene, followed by distillation of solvent from the eluate and re- 3,436,412 Patented Apr. 1, 1969 crystallization of the residue from aqueous methanol, affords 17a ethynyl 3-methylestra-3,5(10),9(11)-trien- 17 3-01 melting at -113. The product has the formula Example 2 acetoxy 17a ethynyl 3 methylestra 1,3,5 (10),9(11) tetraene.A solution of approximately 7 parts of 17 ethynyl 3 methylestra-3,5(10),9(11)-trien- 17,8-01 in a mixture of 200 parts of acetic anhydride and 200 parts of pyridine is heated at 65 for 18 hours, then poured into 3 volumes of ice water. The solid which precipitates is filtered off, washed with water, dried in air, and recrystallized from ether to give Uri-acetoxy- 17a ethynyl 3 methylestra l,3,5(l0),9(11) tetraene melting at -188". The product has the formula OCOCH3 H C Example 3 17a ethynyl 3 methylestra 1,3,5(10),9(11) tetraen-17fi-ol.A mixture of 5 parts of 17/3-acetoxy-17aethynyl-3-methylestra-1,3,5(10),9(1l)-tetraene, 2 parts of potassium hydroxide, 10 parts of water, and 400 parts of methanol is heated at the boiling point under reflux for 1 hour, then chilled and finally poured into 3 volumes of water. The resultant mixture is extracted with ether. The ether extract is dried over anhydrous sodium sulfate and stripped of solvent by vacuum distillation. The residue is 17a-ethynyl-3-methylestra-1,3,5(l0),9(11)-tetraen-l7fl- 01, having the formula Example 4 HaC OH H30 Example 17,3 acetoxy 17a ethynyl 3 phenylestra 1,3,5 (l0),9(1l)-tetraene.A solution of 83 parts of 17aethynyl-3-phenylestra-3,5 ,9 1 1 -trien-17fl-ol in a mixture of 1000 parts of acetic anhydride and 1000 parts of pyridine is maintained at 65 for 25 hours, then poured into 3 volumes of ice Water. The solid precipitate thrown down is collected on a filter, washed with water, dried in air, and recrystallized from ether to give 17,3-acetoxy- 17a ethynyl 3 phenylestra 1,3,5 (10),9(11)-tetraene melting at 227.5-232.5. The product has the formula H30 0 COCH:

: CECE Example 6 3 ethyl 17m ethynylestra 1,3,5(10),8 tetraen- 17fl-ol.To approximately 101 parts of ethylmagnesium bromide dissolved in approximately 175 parts of anhydrous ether is added, with stirring under reflux at a rate such that gentle boiling is maintained, a solution of 4 parts of 17a-ethynyl-17,8-hydroxyestra-4,9( 11)-dien-3-one in a mixture of 45 parts of tetrahydrofuran and 35 parts of anhydrous ether. When the addition is complete, stirring is continued while the reactants are heated at the boiling point under reflux for 6 hours, whereupon the reaction mixture is chilled and then diluted with an equal volume of ice water. The resultant mixture is acidified with approximately 20% hydrochloric acid. The organic phase is separated, washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is chromatographed on silica gel, using benzene and hexane as developing solvents. From an eluate comprising 20% hexane in benzene, on evaporation of solvent, 3-ethyl-17a-ethynylestra-1,3,5(10),8-tet- 4 raen-17fl-ol is obtained as the residue. The product has the formula OH H30 Example 7 1718 acetoxy- 3 ethyl 17 ethynylestra 1,3,5(l0) 8-tetraene.-A solution of 3 parts of 3-ethyl-17a-ethynylestra-1,3,5(10),8-tetraen-17B-ol in a mixture of 50 parts of acetic anhydride and 50 parts of pyridine is maintained at 70 for 63 hours. The resultant mixture is poured into 3 volumes of ice water. The solid which precipitates is collected on a filter, washed thereon with water, and dried in air. Recrystallized from methanol, it melts at 146- 147.5 The product thus isolated is l75-acetoxy-3-ethyl- 17a-ethynylestra-1,3,5(10),8-tetraene, of the formula OCOCHZ H O What is claimed is: 1. A compound of the formula wherein R represents methyl or phenyl and R represents hydrogen or acetyl.

5 6 2. A compound according to claim 1 which is 1711- References Cited ethynyl-3-methy1estra-3,5 10) ,9 11)-trien-17B-o1.

3. A compound according to claim 1 which is 17a- UNITED STATES PATENTS 3,164,617 1/1965 Feather et a1.

ethyny1-3-pheny1estra-3,5( 10) ,9( 11)-trien-17fi-o1.

4. A compound according to claim 1 which is 17 3- 5 HENRY A FRENCH Primary Examiner acetoxy 17a ethynyl 3 methylcstra 1,3,5(10),9 (11)-tetraene.

s. A compound according to claim 1 which is 17;;- acetoxy 3 ethyl 17a-ethyny1estra-1,3,5(10),8-tetraene. 260-999 

1. A COMPOUND OF THE FORMULA 